Targeting Cancer-Associated PCNA with AOH1996 Induces Mitotic Catastrophe and Enhances Cisplatin Therapy in Cervical Cancer

Sep 22, 2026

Cervical cancers remain a major health burden, and toxic side effects limit chemotherapeutic intervention. This study shows that human papillomavirus oncogenes raise a cancer-associated PCNA isoform (caPCNA), with caPCNA abundance specifically elevated in cervical cancer. AOH1996 selectively kills cervical cancer cell line, organoid, and xenograft models by disrupting PCNA–γ-tubulin interactions, causing mitotic arrest and mitotic death in transformed cells. AOH1996 also sensitizes cervical cancer cells to cisplatin, reducing xenograft growth and improving survival with less cisplatin-induced toxicity, supporting AOH1996 as a cisplatin-sensitizing agent.

LanguageEnglish

CategoryResearch & Report

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Pages19

Reading Time48 min

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Abstract

Significance

Introduction

Targeting caPCNA in Cervical Cancer with AOH1996 and Cisplatin

RESEARCH ARTICLE [https://doi.org/10.1158/2767-9764.CRC-25-0648](https://doi.org/10.1158/2767-9764.CRC-25-0648) OPEN ACCESS Targeting Cancer-Associated PCNA with AOH1996 Induces Mitotic Catastrophe and Enhances Cisplatin Therapy in Cervical Cancer Sebastian O. Wendel1, Grant M. Brooke2, Changkun Hu3, Allison R. Sandoval2, Pouya Haratipour4, Long Gu5, Malaney Young5, Maryam Zangi4, Brittany L. Rasche6, N.S. Banerjee7, Jennifer Jossart5, Kelly Garvin8, Brian V. Geisbrecht9, Rachel Cianciolo10, Jacob Cawley8, J. Jefferson P. Perry5, Robert J. Hickey4, Linda H. Malkas5, and Nicholas A. Wallace11 􀀶 ABSTRACT Cervical cancers remain a significant health burden. Limitations on cervical cancer chemotherapeutic intervention caused by toxic side effects are a persistent barrier to care. In this study, we show that the human papillomavirus oncogenes that cause most cervical cancers also increase the levels of a cancer-associated isoform of proliferating cell nuclear antigen (PCNA) known as caPCNA. The abundance of caPCNAis specifically elevated in cervical cancer. Similar to observations in other cancers, we found that a small-molecule inhibitor of caPCNA (AOH1996) selectively killed cell line, organoid, and xenograft models of cervical cancer. Our subsequent molecular analysis identified a novel ability of AOH1996 to induce cell death by disrupting the interaction between PCNA and γ-tubulin, resulting in mitotic arrest. We show AOH1996 selectively induces mitotic death in transformed cells, because these cells attempt to progress through mitosis, rather than decondensing their chromosomes and reforming their nuclear membranes like untransformed control cells. Furthermore, we show that these differences allow AOH1996 to specifically sensitize cervical cancer cells to cisplatin, a frontline chemotherapeutic used to treat cervical cancer. We found that subtherapeutic doses of AOH1996 and cisplatin could reduce cervical cancer xenograft growth and improve survival, similarly to a therapeutic dose of cisplatin without the cisplatin-induced toxicity that restricts care. To our knowledge, this study provides the first evidence that AOH1996 can function as a cisplatin-sensitizing agent in cervical cancer models. Significance: We identify a novel mechanism by which the smallmolecule inhibitor AOH1996 targets cancer-associated PCNA to induce mitotic death in cervical cancer cells. By disrupting PCNA:γ-tubulin interactions, AOH1996 selectively sensitizes tumors to a lower dose ofcisplatin, enabling effective therapy with reduced toxicity and suggesting a potential strategy to reduce treatment-associated toxicity. Introduction Cervical cancer is the fourth most common malignancy among women, accounting for more than 300,000 deaths annually ( 1). Most cervical cancers are caused by persistent infection with high-risk human papillomaviruses (HPV), particularly HPV16 and HPV18, which drive oncogenesis and tumor maintenance through continual HPV oncogene (E6 and E7) expression (2, 3). 1College of Health and Human Science, Kansas State University, Manhattan, Kansas. 2Division of Biology, Kansas State University, Manhattan, Kansas. 3Basic Sciences Division, Howard Hughes Medical Institute, Fred Hutchinson Cancer Center, Seattle, Washington. 4Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California. 5Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California. 6College of Veterinary Medicine, Kansas State University, Manhattan, Kansas. 7Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, Birmingham, Alabama. 8Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado. 9Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas. 10Department of Although HPV vaccination and screening programs can reduce cervical cancer

FAQs

What is caPCNA and how is it connected to cervical cancer?

The study links cervical cancer to increased levels of a cancer-associated PCNA isoform (caPCNA), driven by HPV oncogenes. caPCNA abundance is specifically elevated in cervical cancer.

How does AOH1996 kill cervical cancer cells?

AOH1996 disrupts the interaction between PCNA and γ-tubulin, leading to mitotic arrest. Transformed cells undergo mitotic death rather than reverting to normal nuclear architecture.

How does AOH1996 affect cisplatin therapy?

AOH1996 sensitizes cervical cancer cells to cisplatin, allowing reduced cisplatin doses to decrease xenograft growth and improve survival. The approach aims to achieve effective therapy with reduced cisplatin-induced toxicity.

Sep 22, 2026

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